7-PHENYLSULFONYL-TETRAHYDRO-3-BENZAZEPINE DERIVATIVES AS ANTIPSYCHOTIC AGENTS This invention relates to the novel compound 7- [4- (3-fluoro-4-methyl-benzyl)- benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepine and pharmaceutically acceptable salts and solvates thereof, pharmaceutical compositions containing the compound and salts and solvates thereof and their use in therapy, in particular as antipsychotic agents.

We have now found a novel phenylsulfonyl compound and pharmaceutical acceptable salts and solvates thereof which are useful particularly as antipsychotic agents.

The novel compound of formula (I) and its pharmaceutically acceptable salts and solvates thereof have high affinities at desired receptors, exhibits good in vivo profiles and have good Drug Metabolism and Pharmacokinetics (DMPK) properties.

Therefore, in a first aspect of the invention, there is provided one or more chemical entities selected from 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1 H-3-benzazepine and a pharmaceutical acceptable salt and solvate thereof.

The structure of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl- 2,3, 4, 5-tetrahydro-1H-3-benzazepine is indicated below as the compound of formula (I) : As used hereinafter, the terms"compound", "compound of formula (I)"or"compound of the present invention"refer to the compound 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepine (free base) and pharmaceutical acceptable salts and solvates thereof.

As used herein, the term"solvate"refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. For example, the solvent used is water and the resulting solvate may also be referred to as a hydrate.

It will be appreciated that for use in medicine the salts of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutical acceptable salts will be apparent to

those skilled in the art and include for example acid addition salts formed with inorganic acids e. g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e. g. succinic, maleic, malic, mandelic, acetic, fumaric, glutamic, lactic, citric, tartaric, benzoic, benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Examples of salts of compounds of formula (I) include the hydrochloride, maleate, tosylate or mesylate salts or pharmaceutically acceptable solvates thereof. Other non-physiologically acceptable salts e. g. oxalates, may be used, for example in the isolation of a compound of formula (I) and are included within the scope of this invention. The scope of the invention includes salts, solvates and hydrates of the compound of formula (I).

The compound of formula (43 may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non- stoichiometric forms thereof.

In a further aspect of the invention, there is provided one or more chemical entities selected from a salt of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1 H-3-benzazepine and solvates thereof.

In a yet further aspect of the invention, there is provided one or more chemical entities selected from the tosylat salt of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepine and solvates thereof.

Depending on the solvent from which the tosylat is recovered, the tosylat may be obtained as a solvate and such a solvate also forms one aspect of the present invention. The solvate may be a pharmaceutical acceptable solvate. Suitable solvates include hydrates, such as monohydrate and trihydrate solvates.

Alternatively, tosylat is obtained as an anhydrate. The anhydrate may contain less than 2% water, for example less than 1 % water.

In another aspect there is provided one or more chemical entities selected from the tosylat and a pharmaceutical acceptable solvate thereof in isolated form. In a further aspect there is provided one or more chemical entities selected from the tosylat and a pharmaceutical acceptable solvate thereof which is substantially free of alternative salts, alternative solvates or free base of a compound of formula (I) or other impurity.

By"substantially free of alternative salts, alternative solvates or free base of 7- [4- (3-fluoro-4- methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepine or other impurity"is meant containing less than 10%, for example less than 5%, such as less than 2%, of alternative salts, alternative solvates or free base of 7- [4- (3-fluoro-4-methyl- benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine or other impurity. The term"other impurity"includes any compound other than the 7- [4- (3-fluoro-4- methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepine.

The tosylat and a pharmaceutically acceptable solvate thereof may each be obtained in a non-crystalline or crystalline or alternative polymorphic form.

Such different forms of salts and solvates are intended to be included within the scope of this invention.

Therefore, in yet a further aspect of the invention, there is provided a tosylat hydrate of a compound of formula (I), for example, tosylat monohydrate or tosylat trihydrate.

7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5-tetrahydro-1 H- 3-benzazepine free base may be prepared by the following process as set forth below or by processes disclosed in W003/99786 which is incorporated herein by reference.

When preparing a compound of formula (I), precursors to the compound of formula (I) may possess a suitable protecting group R on the nitrogen atom of the benzazepine ring, (for example a t-butyloxycarbonyl group [BOC]), instead of the methyl group. Such protecting groups are used for example when it is easier to introduce the methyl substituent at the end of a synthetic route.

In a further aspect of the invention, there is provided a general process (A) for preparing the compound of formula (I) which process comprises: coupling a compound of formula (II) with a compound of formula (III) in a suitable solvent, such as tetrahydrofuran (THF), wherein Y is zinc halide such as zinc chloride (ZnCI) or zinc bromide (ZnBr), R is methyl or a suitable protecting group as described hereinbefore, and W is a leaving group, such as chloro, bromo, iodo, or trifluoromethanesulfonate, in the presence of a palladium catalyst, for example palladium tetrakis (triphenylphosphine) [(Pd (Ph3) 4] optionally at elevated temperature e. g. 60°C ; and thereafter optionally for process (A):

removing any protecting groups; converting the hydrogen on the nitrogen atom of the benzazepine ring to a methyl group if applicable ; and/or forming a pharmaceutically acceptable salt or solvate.

An example of the above general process is: W is Br and Y is ZnCI which can be conveniently carried out in an inert solvent e. g. tetrahydrofuran in the presence of palladium tetrakis (triphenylphosphine) at elevated temperature e. g. 60°C.

The present invention also provides a general process (B) for preparing the compound of formula (I) which process comprises: reacting a compound of formula (IV) with a compound of formula (V) wherein L is a leaving group, such as fluoro, chloro, C1 6alkoxy or aryloxy, R is methyl or a suitable protecting group as described hereinbefore and M is a metal, such as lithium or magnesium; and thereafter optionally for process (B): removing any protecting groups; 'converting the hydrogen on the nitrogen atom of the benzazepine ring to a methyl group if applicable ; and/or forming a pharmaceutically acceptable salt or solvate.

This general method (B) can be conveniently performed by mixing the two components at preferably-78°C to room temperature in a suitable solvent such as tetrahydrofuran or ether for 10 minutes to 18 hours. Removal of certain R protecting groups e. g. trifluoroacetyl, can also take place simultaneously during this process.

Compounds of formula (II) may be prepared by reacting a compound of formula (VI)

with 4-bromobenzenesulfonyl chloride in the presence of a Lewis acid, for example, indium (ill) trifluromethanesulfonate, tin (II) trifluromethanesulfonate, bismuth (ill) chloride, or indium (fil) chloride, or mixtures thereof, and trifluoromethanesulfonic acid in a suitable solvent, for example, trifluoroacetic acid and, optionally, a co-solvent, for example dichloromethane.

Compounds of formula (ici) may be prepared according to known methods and/or are commercially available.

Compounds of formula (IV) may be prepared by known processes, for example, chlorosulfonation of the aromatic ring of the benzazepine using chlorosulfonic acid.

Conversion to the sulfonyl fluoride can be achieved, if required, by reaction with potassium fluoride in acetonitrile at room temperature. Suitable examples of an R group are methyl or protecting groups such as a trifluoroacetyl group.

Compounds of formula (V) may be prepared by metallation of compounds of formula (Vil) wherein L is bromo, for example by treatment with n-butyllithium at-78°C in a suitable solvent such as tetrahydrofuran.

A compound of formula (VI) may be prepared using methods as described in the literature, for example using the route as described in European Patent EP285287.

Compounds of formula (VII) may be prepared from 2-fluoro-4-bromotoluene, which is commercially available. Metallation by treatment with n-butyllithium in a suitable inert solvent such as tetrahydrofuran at-78°C or by formation of the corresponding Grignard reagent with magnesium turnings, followed by addition into 4-bromobenzaldehyde gives the corresponding benzhydrol. This in turn may be converted to the compound of formula (Vll) wherein L is Br by treatment with triethylsilane and trifluoromethanesulfonic acid in an inert solvent such as chloroform, at 0°C to ambient temperature.

Interconversion of an R group to a methyl group typically arises when a compound of formula (Vlll)

wherein R is other than a methyl group, is used as a precursor to the compound of formula (I), or when it is easier to introduce the methyl substituent at the end of a synthetic sequence.

For example, conversion of R from a t-butoxycarbonyl (BOC) group to hydrogen is conducted by the treatment of the N-BOC protected compound with hydrogen chloride in ethanol or dioxan at room temperature.

Conversion of R from hydrogen to methyl is conducted by the treatment of the NH compound with formaldehyde in dichloroethane in the presence of a reducing agent, such as sodium triacetoxyborohydride, or by the treatment of the NH compound with the appropriate methyl halide, such as iodomethane, under standard alkylation conditions [potassium carbonate in dimethylformamide (DMF) at 40°C].

In a still further aspect of the invention there is provided a process for the preparation of the tosylat salt of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1 H-3-benzazepine comprising reacting 7- [4- (3-fluoro-4-methyl-benzyl)-benzene- sulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepine with anhydrous p- toluenesulfonic acid in a suitable solvent, for example, ethyl acetate, tetrahydrofuran or acetic acid, at optionally elevated temperature, e. g. 60°C.

Solvates of a salt of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl- 2,3, 4, 5-tetrahydro-1H-3-benzazepine may be prepared by conventional means from a solution of the salt of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl- 2,3, 4, 5-tetrahydro-1H-3-benzazepine. For example, the monohydrate solvate of the tosylat salt may be prepared by reaction of 7- [4- (3-fluoro-4-methyl-benzyl)-benzene-sulfonyl]-8- methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepine with p-toluenesulfonic acid monohydrate in a suitable solvent, for example ethyl acetate, methanol, tetrahydrofuran or water, either at room temperature or elevated temperatures (for example up to the boiling point of the solvent used).

Anhydrous p-toluenesulfonic acid in acetic acid and p-toluenesulfonic acid monohydrate are commercially available.

As used herein, the phrase"7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3- methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine and a pharmaceutical acceptable salt and solvate thereof'is intended to mean 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-

methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine or a pharmaceutical acceptable salt or a pharmaceutically acceptable solvate independently or mixtures of 7- [4- (3-fluoro-4- methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine, one or more pharmaceutical acceptable salts and one or more pharmaceutical acceptable solvates.

Description of Figures : Figure) shows X-Ray powder diffraction (XPRD) data obtained for 7- [4- (3-fluoro-4-methyl- benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepinium tosylat prepared as described in Example 3.

The 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5-tetrahydro- 1H-3-benzazepinium tosylate as described in Example 3 is characterised by having an XRPD pattern with signals substantially as listed in Table 1.

Figure 2 shows the Raman spectrum of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepinium tosylat prepared as described in Example 3.

Figure 3 shows a DSC thermogram of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepinium tosylate prepared as described in Example 3.

Figure 4 shows X-Ray powder diffraction (XPRD) data obtained for 7- [4- (3-fluoro-4-methyl- benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepinium tosylat, monohydrate prepared as described in Example 4.

The 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5-tetrahydro- 1H-3-benzazepinium tosylate, monohydrate as described in Example 4 is characterised by having an XRPD pattern with signals substantially as listed in Table 2.

Figure 5 shows the Raman spectrum of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepinium tosylate, monohydrate prepared as described in Example 4.

Figure 6 shows a DSC thermogram of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepinium tosylate, monohydrate prepared as described in Example 4.

It will be recognised that spectra and diffraction data will vary slightly according to various factors such as the temperature, concentration and instrumentation used. The skilled person will recognise that XRPD peak positions are affected by differences in sample height. The peak positions quoted herein are thus subject to a variation of +/-0. 15 degrees 2-theta.

In another aspect of the present invention there is provided the anhydrous tosylate salt of 7- [4- (4-chlorobenzyloxy)-benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine characterised in that it provides an XRPD spectrum substantially as illustrated in Figure 1.

In a further aspect of the present invention there is provided the anhydrous tosylat salt of 7- [4- (4-chlorobenzyloxy) benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine characterised in that it provides an XRPD spectrum with signals substantially as listed in Table 1.

In another aspect of the present invention there is provided the monohydrate, tosylate salt of 7- [4- (4-chlorobenzyloxy)-benzenesulfonyl]-8-methoxy-3-methyl-2, 3, 4, 5-tetrahydro-1 H-3- benzazepine characterised in that it provides an XRPD spectrum substantially as illustrated in Figure 4.

In a further aspect of the present invention there is provided the monohydrate, tosylat salt of 7- [4- (4-chlorobenzyloxy) benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine characterised in that it provides an XRPD spectrum with signals substantially as listed in Table 2.

7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5-tetrahydro-1 H- 3-benzazepine and its pharmaceutical acceptable salts and solvates thereof have antagonist affinity for dopamine receptors, in particular the D3 and D2 receptors, and is useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. The compound of formula (I) and its pharmaceutically acceptable salts and solvates thereof have also been found to have greater affinity for dopamine D3 than for D2 receptors. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted via blockade of D2 receptors; however this mechanism is also thought to be responsible for undesirable extrapyramidal side effects (eps) associated with many neuroleptic agents. Without wishing to be bound by theory, it has been suggested that blockade of the dopamine D3 receptor may give rise to beneficial antipsychotic activity without significant eps (see for example Sokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, Clinical Neuropharmacology, Vol 16, No. 4,295-314, 1993).

The compound of formula (I) and its pharmaceutical acceptable salts and solvates thereof have also been found to exhibit affinity for the serotonin 5-HT2C, 5-HT2A and 5-HTg receptors. These properties may give rise to anti-psychotic activity (e. g. improved effects on cognitive dysfunction) activity with reduced eps, and/or anxiolytic/antidepressant activity.

These could include, but are not limited to, attenuation of cognitive symptoms via 5-HT6 receptor blockade (see Reavill, C. and Rogers, D. C. , 2001, Investigational Drugs 2,104- 109), and reduced anxiety (see for example Kennett et al., Neuropharmacology 1997 Apr-

May; 36 (4-5): 609-20), protection against eps (Reavill et al., Brit. J. Pharmacol., 1999; 126: 572-574) and antidepressant activity (Bristow et al., Neuropharmacology 39: 2000; 1222- 1236) via 5-HT2c receptor blockade. <BR> <BR> <BR> <BR> <BR> <BR> <P>7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3, 4, 5-tetrahydro-1 H- 3-benzazepine and its pharmaceutically acceptable salts and solvates thereof may also exhibit affinity for other receptors not mentioned above, resulting in beneficial antipyschotic activity.

7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5-tetrahydro-1 H- 3-benzazepine and its pharmaceutically acceptable salts and solvates thereof are of use in the treatment of psychotic disorders.

In a further aspect therefore, the invention provides one or more chemical entities selected from 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1H-3-benzazepine and a pharmaceutical acceptable salt and solvate thereof for use in therapy.

In another aspect, the invention provides one or more chemical entities selected from 7- [4- (3- fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl- 2, 3,4, 5-tetrahydro-1 H-3- benzazepine and a pharmaceutically acceptable salt and solvate thereof for use in the treatment of a condition which requires modulation of a dopamine D3 receptor.

In another aspect, the invention provides one or more chemical entities selected from 7- [4- (3- fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl- 2, 3,4, 5-tetrahydro-1 H-3- benzazepine and a pharmaceutically acceptable salt and solvate thereof for use in the treatment of psychotic disorders.

In another aspect, the invention provides the use of one or more chemical entities selected from 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1H-3-benzazepine and a pharmaceutically acceptable salt and solvate thereof in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine D3 receptor.

In another aspect, the invention provides the use of one or more chemical entities selected from 7- [4- (3-fluoro-4-methyl-benzyi)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1H-3-benzazepine and a pharmaceutically acceptable salt and solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders.

In another aspect, the invention provides a method of treating a condition which requires modulation of a dopamine D3 receptor, which comprises administering to a mammal in need thereof an effective amount of one or more chemical entities selected from 7- [4- (3-fluoro-4-

methyl-benzyl)-benzenesulfOnyl]-8-methoxy-3-methyl-2a3X4X5-t etrahydro-1 H-3-benzazepine and a pharmaceutical acceptable salt and solvate thereof.

In another aspect, the invention provides a method of treating psychotic disorders which comprises administering to a mammal in need thereof an effective amount of one or more chemical entities selected from 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy- 3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine and a pharmaceutical acceptable salt and solvate thereof.

Within the context of the present invention, the terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.

Within the context of the present invention, the term"psychotic disorder"includes Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60) ; Schizophreniform Disorder (295.40) ; Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8) ; Shared Psychotic Disorder (297.3) ; Psychotic Disorder Due to a General-Medical Condition including the subtypes With Delusions and With Hallucinations ; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81) and With Hallucinations (293.82) ; and Psychotic Disorder Not Otherwise Specified (298.9).

7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5-tetrahydro-1 H- 3-benzazepine and its salts and solvates thereof may also be of use in the treatment of the following disorders:- Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296. 80) ; Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90) :

Anxiety disorders including Social Anxiety Disorder, Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type, Natural Environment Type, Blood-Injection-injury Type, Situational Type and Other Type), Social Phobia (300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified (300.00) : Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance- Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance- Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-induced Anxiety Disorder, Substance-induced Sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks) ; Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9) ; Amphetamine (or Amphetamine- Like)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-induced Anxiety Disorder, Amphetamine-induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9) ; Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9) ; Cannabis- Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-Induced Psychotic Disorder, Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9) ; Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine- Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9) ; Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292. 89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9) ; Inhalant-

Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305. 90), Inhalant Intoxication (292. 89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9) ; Nicotine- Related Disorders such as Nicotine Dependence (305. 1), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9) ; Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-induced Psychotic Disorder, Opioid- Induced Mood Disorder, Opioid-induced Sexual Dysfunction, Opioid-Induced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9) ; Phencyclidine (or Phencyclidine-Like)-Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-Induced Mood Disorder, Phencyclidine-Induced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9) ; Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic- Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-induced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-induced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-induced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-induced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic- Related Disorder Not Otherwise Specified (292.9) ; Polysubstance-Related Disorder such as Polysubstance Dependence (304.80) ; and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide: Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307. 45) and Dyssomnia Not Otherwise Specified (307.47) ; primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47) ; Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44) ; Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type: Eating disorders such as Anorexia Nervosa (307.1) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50) :

Autistic Disorder (299.00) ; Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit/Hyperactivity Disorder Combined Type (314.01), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9) ; Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23) : Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301,81), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9) : Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e. g. Alzheimer's disease: and Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79) ; sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72) ; orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75) ; sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51) ; Sexual Dysfunction Not Otherwise Specified (302.70) ; paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302. 84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9) ; gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85) ; and Sexual Disorder Not Otherwise Specified (302.9).

All of the various forms of the psychotic disorders mentioned herein are contemplated as part of the present invention.

"Treatment"includes prophylaxis, where this is appropriate for the relevant condition (s).

It will be appreciated by those skilled in the art that 7- [4- (3-fluoro-4-methyl-benzyl)- benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepine or a salt or solvate thereof according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, 5HT3 antagonists, serotonin agonists,

NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), non-selective reuptake inhibitors of one or more of serotonin, noradrenaline and norepinephrine, CRF-1 antagonists, tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HTrA antagonists, 5HT, s antagonists, 5HT, antagonists, 5HT4 partial agonists, D1 agonists, M1 agonists, anticonvulsant agents, non-steroidal anti- inflammatory drugs (NSAIDs) and/or cyclooxygenase-2 (COX-2) inhibitors.

It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.

Suitable 5HT3 antagonists which may be used in combination with the compound of the invention for example one or more chemical entities selected from ondansetron, granisetron and metoclopramide.

Suitable serotonin agonists which may be used in combination with the compound of the invention include for example one or more chemical entities selected from sumatriptan, rauwolscine, yohimbine and metoclopramide.

Suitable SSRts which may be used in combination with the compound of the invention include for example one or more chemical entities selected from fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline and zimeldine.

Suitable SNRts which may be used in combination with the compound of the invention include for example one or more chemical entities selected from venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination with the compound of the invention include for example one or more chemical entities selected from imipramine, amitriptiline, chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combination with the compound of the invention include for example one or more chemical entities selected from bupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of the compound of the invention include for example one or more chemical entities selected from divalproex, carbamazepine and diazepam.

Suitable NSAID agents which may be used in combination with the compound of the invention include for example one or more chemical entities selected from ibuprofen, aspirin and its active metabolite salicylate.

Suitable COX-2 inhibitors include rofecoxib (available under the tradename VIOXX@, from Merck, US patent number 5,474, 995); celecoxib (available under the tradename CELEBREX (E), from Pfizer, US patent number 5,466, 823); valdecoxib (available under the tradename EXTRA@, from Pfizer, US patent number 6,633, 272); etoricoxib (available under the tradename ARCOXIA@, from Merck, US patent number 5, 861, 419); lumiracoxib (available under the tradename PREX) GE@, from Novartis); paracoxib (US patent number 5,932, 598) ; COX-189 from Novartis; BMS347070 from Bristol Myers Squibb; tiracoxib (JTE522) from Japan Tobacco; ABT963 from Abbott; CS502 from Sankyo; 2- (4- ethoxyphenyl)-3- (3-methanesulfonylphenyl)-pyrazolo [1, 5-b] pyridazine (GlaxoSmithKline) and 2-butoxy-4- [4- (methylsulfonyl) phenyl]-6- (trifluoromethyl) pyrimidine (GlaxoSmithKline).

The compound of formula (I) and its pharmaceutical acceptable salts and solvates thereof are also suitable for combination with other typical and atypical antipsychotics to provide improved treatment of psychotic disorders. Particular advantages associated with the combinations, uses and methods of treatment of the compound of formula (I) and its pharmaceutical acceptable salts and solvates thereof include equivalent or improved efficacy at doses of administration which are lower than those commonly used for the individual components. Improved treatments of positive symptoms and/or negative symptoms and/or cognitive symptoms of the psychotic disorder may also be observed. The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to treatment with certain antipsychotic agents (also known as neuroleptic agents).

The combination therapies of the invention may be administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add- on therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof and at least one antipsychotic agent are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilised on a therapeutic administration of one or more of the components for a period of time and then receives administration of another component. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may be administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one antipsychotic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one antipsychotic agent to patients who are receiving administration of the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof.

The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regime wherein the individual components

are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.

In a further aspect therefore, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof to a patient receiving therapeutic administration of at least one antipsychotic agent. In a further aspect, the invention provides the use of the compound of formula (1) or a pharmaceutical acceptable salt or solvate thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent. The invention further provides the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.

In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof. In a further aspect, the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of the compound of formula (1) or a pharmaceutical acceptable salt or solvate thereof. The invention further provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof.

In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof in combination with at least one antipsychotic agent. The invention further provides the use of a combination of the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides the compound of formula (I) or a pharmaceutical acceptable salt thereof for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder.

The invention further provides the use of at least one antipsychotic agent in the manufacture

of a medicament for simultaneous therapeutic administration with the compound of formula (I) or a pharmaceutical acceptable salt thereof in the treatment of a psychotic disorder.

In further aspects, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more further dosage forms each comprising a antipsychotic agent for simultaneous therapeutic administration.

Examples of antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol ; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene ; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles ; dibenzothiazepines; imidazolidinones ; benzisothiazolyl-piperazines ; triazine such as lamotrigine ; dibenzoxazepines, such as loxapine ; dihydroindolones, such as molindone ; aripiprazole ; and derivatives thereof that have antipsychotic activity.

Examples of tradenames and suppliers of selected antipsychotic drugs that are suitable for use in the present invention are as follows : clozapine (available under the tradename CLOZARILO, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREXA, from Lilly ; ziprasidone (available under the tradename GEODONO, from Pfizer); risperidone (available under the tradename RISPERDAL@, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL@, from AstraZeneca); sertindole (available under the tradename SERLECT@) ; amisulpride (available under the tradename SOL) ON@, from Sanofi-Synthelabo) ; haloperidol (available under the tradename HALDOL@, from Ortho-McNeil) ; haloperidol decanoate (available under the tradename HALDOL decanoate@) ; haloperidol lactate (available under the tradenames HALDOLO and INTENSOL@) chlorpromazine (available under the tradename THORAZINEO, from SmithKline Beecham (GSK); fluphenazine (available under the tradename PROLIXIN@, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); fluphenazine decanoate (available under the tradename PROLIXIN decanoate@) ;

fluphenazine enanthate (available under the tradename PROLIXIN@) ; fluphenazine hydrochloride (available under the tradename PROLIXINO) ; thiothixene (available under the tradename NAVANEM) ;, from Pfizer); thiothixene hydrochloride (available under the tradename NAVANE@) ; trifluoperazine (10- [3- (4-methyl-1-piperazinyl) propyl]-2- (trifluoromethyl) phenothiazine dihydrochloride, available under the tradename STELAZINE, from SmithKline Beckman; perphenazine (available under the tradename TR) LAFON@ ; from Schering); perphenazine and amitriptyline hydrochloride (available under the tradename ETRAFON TRILAFONO) ; thioridazine (available under the tradename MELLARIL@ ; from Novartis, Roxane, HiTech, Teva, and Alpharma) ; molindone (available under the tradename MOBAN@, from Endo); molindone hydrochloride (available under the tradename MOBAN#) ; loxapine (available under the tradename LOXITANE (D ; from Watson); loxapine hydrochloride (available under the tradename LOXITANE@) ; and loxapine succinate (available under the tradename LOXITANEt@). Furthermore, benperidol (Glianimon@), perazine (Taxi) an@) or melperone (Eunerpan@)) may be used.

Other suitable antipsychotic drugs include promazine (available under the tradename SPARINE@), triflurpromazine (available under the tradename VESPRIN@), chlorprothixene (available under the tradename TARACTAN), droperidol (available under the tradename INAPSINE), acetophenazine (available under the tradename TINDAL@ ; ), prochlorperazine (available under the tradename COMPAZINEO), methotrimeprazine (available under the tradename NOZINAN@), pipotiazine (available under the tradename PIPOTRIL@), iloperidone, pimozide and flupenthixol.

In one further aspect of the invention, suitable antipsychotic agents include olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

For use in medicine, the compound of the present invention is usually administered as a standard pharmaceutical composition. Therefore in a further aspect of the present invention there is provided a pharmaceutical composition comprising one or more chemical entities selected from 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1 H 3-benzazepine and a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier. The pharmaceutical composition can be for use in the treatment of any of the conditions described herein.

The compound of the invention may be administered by any convenient method, for example by oral, parenteral (e. g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

The compound of the invention as hereinbefore described and its pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutical acceptable salt in a suitable liquid carrier (s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier (s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule ; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier (s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutical acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.

Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

The composition is suitably in unit dose form such as a tablet, capsule or ampoule.

The pharmaceutical acceptable compound of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 250 mg, for example between 1 mg and 150 mg, such as between 2 mg and 100 mg, e. g. between 2 and 50 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, such as between 0.1 mg and 50 mg, e. g. between 1 and 25 mg of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5-tetrahydro- 1 H 3-benzazepine or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compound will be administered for a period of continuous therapy, for example for a week or more.

Biological Test Methods Binding experiments on cloned dopamine (e. q. D2 and D3) receptors The ability of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1H-3-benzazepine or a salt or solvate thereof to bind selectively to human D2/D3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors.

The inhibition constants (Ki) of test compounds for displacement of [1251]-lodosulpride binding to human D2/D3 receptors expressed in CHO cells were determined as follows. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation.

Cell pellets were stored frozen at-80°C. Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding.

Preparation of CHO cell membranes: Cell pellets were gently thawed at room temperature, and resuspended in about 20 volumes of ice-cold Extraction buffer; 5mM EDTA, 50mM Trizma pre-set crystals (pH7. 4@37°C), 1mM MgCl2, 5mM KCI and 120mM NaCI. The suspension was homogenised using an Ultra-Turrax at full speed for 15 seconds. The homogenate was centrifuged at 18,000 r. p. m for 15 min at 4°C in a Sorvall RC5C centrifuge.

Supernatant was discarded, and homogenate re-suspended in extraction buffer then centrifugation was repeated. The final pellet was resuspended in 50mM Trizma pre-set crystals (pH 7.4 @ 37°C) and stored in 1ml aliquot tubes at-80°C (D2 = 3. 0E+08 cells, D3 = 7. 0E+07 cells and D4 = 1. 0E+08 cells). The protein content was determined using a BCA protocol and bovine serum albumin as a standard (Smith, P. K. , et al., Measurement of protein using bicinchoninic acid. Anal. Biochem. 150,76-85 (1985) ).

Binding experiments : Crude D2/D3 cell membranes were incubated with 0.03nM [125I]- lodosulpride (-2000 Ci/mmol ; Amersham, U. K. , and the test compound in a buffer containing 50mM Trizma pre-set crystals (pH 7.4 @ 37°C), 120mM NaCl, 5mM KCI, 2mM CaCl2, 1mM MgCl2, 0.3% (w/v) bovine serum albumin. The total volume is 0. 2ml and incubated in a water bath at 37°C for 40 minutes. Following incubation, samples were filtered onto GF/B Unifilters using a Canberra Packard Filtermate, and washed four times with ice-cold 50mM Trizma pre-set crystals (pH 7.4 @ 37°C). The radioactivity on the filters was measured using a Canberra Packard Topcount Scintillation counter. Non-specific binding was defined with 10µM SKF-102161 (YM-09151). For competition curves, 10 serial log concentrations of competing cold drug were used (Dilution range: 10µM-10pM).

Competition curves were analysed using Inflexion, an iterative curve fitting programme in Excel. Results were expressed as pKi values where pKi = -log10 [Ki].

The exemplified compound has a pKi value of # 8.0 at the dopamine D3 receptor.

The exemplified compound has a pKi value of 7. 0 at the dopamine Dz receptor.

Binding experiments on cloned 5-HT6 receptors Compounds can be tested following the procedures outlined in WO 98/27081.

The exemplified compound has a pKi value of 8. 0 at the serotonin 5-HT6 receptor.

Binding experiments on cloned 5-HT ? A and 5-HT receptors Compounds can be tested following the procedures outlined in WO 94/04533.

The exemplified compound has a pKj value of #8. 0 at the serotonin 5-HT2c receptor and : 8. 0 at the serotonin 5-HT2A receptor.

The invention is further illustrated by the following non-limiting examples : Description 1 1- (4-Bromo-phenyl)-1- (3-fluoro-4-methylphenyl)-methanol (D1) Dried magnesium turnings (4.24 g, 0.55 mole) were stirred with a heavy stirrer bar under argon for 16 hours. A few crystals of iodine were added followed by the addition a solution of 4-bromo-2-fluorotoluene (94.5 g, 0.5 mole) in tetrahydrofuran [THF] (200 ml). This addition took place over about 40 minutes and the solution was allowed to reflux during the addition.

The resulting solution was stirred for 1 hour. 4-Bromobenzaldehyde (71.7 g 0.39 mole) in THF (200 ml) was cooled to 0°C then treated with the above Grignard solution. The addition

of the Grignard solution took place over 30 minutes and the resulting solution was stirred for 2 hours at room temperature. The reaction mixture was poured slowly into a solution of potassium sodium tartrate (10% solution, 1 L) and extracted with ethyl acetate (EtOAc). The organic solution was dried with brine and sodium sulfate and evaporated. Trituration with hexane gave the title compound (D1) as a white solid (71.8 g, 65%). 1H NMR: aH (CDCI3) 2.20 (1 H, d), 2.24 (3H, m), 5.75 (1 H, d), 6.98 (1H, s) 7.05 (1H, m), 7.16 (1H, m), 7.24 (2H, m) 7.47 (2H, m).

Description 2 1- (4-Bromo-phenyl)-I- (3-fluoro-4-methylphenyl)-methane (D2) A solution of 1- (4-bromophenyl)-1- (3-fluoro-4-methylphenyl)-methanol (21.4 g, 0.072 mole), triethylsilane (34 g, 0.29 mole) and chloroform (300 ml) was cooled in an ice bath. Trifluoromethanesulfonic acid (7 ml, 0.78 mole) was added over 30 minutes. The solution was stirred for 1 hour then washed with saturated sodium bicarbonate solution and brine.

The solvent was removed under reduced pressure and the residue was distilled. Triethylsilanol distills first Bp (75°C @0. 2mmHg). The title compound (D2) distills Bp (125- 132°C@ 0. 15mmHg). Yield (16. 4 g, 82%)'H NMR: 8H (CDCI3) 2.23 (3H, m), 3.86 (2H, s), 6. 8 (2H, m) 7.0 (3H, m), 7.4 (2H, m).

Description 3 8-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride (D3) a) 7-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine A mixture of 7-methoxy-2, 3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (see EP 285287) (25 g, 125 mmol) and 37% formalin (25 ml) in dichloroethane (250 ml) was treated with sodium triacetoxyborohydride (30 g, 250 mmol) keeping the internal temperature below 20°C. After stirring for 2 hours, water was added and the pH adjusted to 10 using 50% sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness to afford the product (23 g). b) 8-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine-7-sulfonic acid The product from part (a) (23 g) was dissolved in trifluoroacetic acid (125 ml), and then stirred in an ice bath while chlorosulfonic acid (16.5 ml, 250 rrimol) was added dropwise.

The solution was stirred for 30 minutes, then evaporated to dryness to afford the title sulfonic acid which was used directly in the next step. c) 8-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride The sulfonic acid from part (b) was dissolved in thionyl chloride (75 mi) and the solution refluxed for 30 minutes. After cooling, the solution was evaporated to dryness to afford the title sulfonyl chloride which was used directly in the next step. d) 8-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride The sulfonyl chloride from part (c) was dissolved in acetonitrile (500 ml) and potassium fluoride (37 g, 625 mmol) and 18-crown-6 (1 crystal) were added. The mixture was stirred for 18 hours, then quenched with cold aqueous sodium bicarbonate solution until the pH equalled 8. The mixture was extracted twice with ethyl acetate, washed with bicarbonate solution then brine, dried and evaporated to afford the sulfonyl fluoride D3 (25 g). MH+274'H NMR: 8H (DMSO-d6) 2.35 (3H, s), 2.61 (4H, m), 2.95 (2H, m), 3.03 (2H, m), 3.97 (3H, s), 7.29 (1H, s), 7.69 (1H, s).

Description 4 7- (4-Bromobenzenesulfonyl)-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepine (D4) Trifluoromethanesulfonic acid (8.8 mL) was added to a mixture of 7-methoxy-3-methyl- 2,3, 4, 5-tetrahydro-1H-3-benzazepinium trifluoroacetate (20 g, 65.5 mmol), 4-bromobenzene- sulfonyl chloride chloride (25 g, 97.8 mmol), and indium (ill) chloride (1.44 g, 6.5 mmol) in trifluoroacetic acid (60 mL), under a nitrogen atmosphere. The resulting mixture was heated under reflux for 24 hours then cooled, diluted with dichloromethane (200 mL), and methanol (100 mL) added maintaining the temperature below 25°C. 20% (w/v) Aqueous sodium hydroxide (200 mL) was added over 1 hour, maintaining the temperature below 25°C, to pH 12 and the phases separated. The aqueous phase was extracted with dichloromethane (60 mL) and the combined organic phases, washed with water (60 mL) and diluted with isopropyl acetate (300 mL). The solution was distilled under vacuum and the resulting slurry cooled to ambient temperature and stirred for 4 hours. The solid was filtered, washed with isopropyl acetate (40 mL) and dried under vacuum at 40°C to give the title product (D4) as a white solid (19 g). Mp 161-163°C ; MH+ 410 and 412 ;'H NMR 5H (400 MHz, DMSO-d6) 2.25 (3H, s), 2.40-2. 50 (4H, m), 2.85-2. 95 (4H, m), 3.72 (3H, s), 7 » 00 (1H, s), 7.72 (1H, s), 7.80 (1H, s).

Example 1 7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-IH-3-benzazepine (EI)

To a stirred solution of 1-(4-bromo-phenyl)-1-(3-fluoro4-methylphenyl)-methane (D2) (46.45 g, 166.6 mmol) in dry THF (300 ml) at-78°C under argon was added dropwise n-butyl lithium ([BuLi] (2.5M in hexane, 66.5 ml, 166.4 mmol). The resulting solution was stirred for 30 minutes at-78°C before the dropwise addition of 8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H- 3-benzazepine-7-sulfonyl fluoride (D3) (15.16 g, 55.47 mmol) in dry THF (150 ml). The addition was carried out over 20 minutes. The resultant red solution was stirred at-78°C for 1hour then quenched with acetic acid (10 mi). The mixture was diluted with water (200 ml) and allowed to warm to room temperature. The pH was adjusted to greater than 7 using saturated sodium hydrogen carbonate and extracted with EtOAc (2 x 300 ml). The combined organic phase was washed with water, brine and the dried over magnesium sulfate then concentrated to give an oil. This oil was purified using column chromatography over silica, eluting with 10% ammonia in methanol-dichloromethane (0 to 10%) yielding an off white solid (23.0 g). Further purification was carried out using amino column chromatography, eluting with 0 to 100% EtOAc in hexane. This yielded the title compound (E1), free base, as a white solid (18.3 g, 73%). MH+ 454 ;'H NMR 5H (CDCI3) 2.22 (3H, s), 2.36 (3H, s), 2.48- 2.58 (4H, m), 2.85-2. 99 (4H, m), 3.73 (3H, s), 3.96 (2H, s), 6.63 (1H, s), 6.68-6. 84 (2H, m), 7.03-7. 12 (1H, t), 7.20-7. 29 (3H, m), 7.80 (1H, s), 7.85-7. 93 (2H, d).

Example 2 7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1H-3-benzazepine hydrochloride (E2) To a solution of the free base of 7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine (E1) in dichloromethane/methanol was added HCI (1M in ether, 40.3 ml, 40.3 mmol). Evaporation followed by trituration with ether yielded the title compound as the monohydrochloride salt (19.52 g). MH+454 ; 1H NMR #H (DMSO-d6) 2.17 (3H, s), 2.76 (3H, d), 2.80-3. 60 (8H, complex series of multiplets), 3.72 (3H, s), 4.00 (2H, d), 6.90-7. 01 (2H, m), 7.02 (1H, d), 7.19 (1H, t), 7.44 (2H, d), 7.79-7. 83 (3H, m).

Example 3 7- 14-(3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-m ethyl-2, 3,4, 5- tetrahydro-1H-3-benzazepinium p-toluenesulfonate (E3)

A 12% w/w solution of p-toluenesulfonic acid in acetic acid (0.59 mL) was added to a solution of 7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5-tetrahydro- 1H-3-benzazepine (E1) (0.20 g) in a mixture of THF (2 mL) and ethyl acetate (2 mL). The solution was seeded and the solvent allowed to evaporate slowly. The resulting solid was filtered and dried under vacuum at 40°C to give the title product (E3) as a white solid (0.18 g). Mp 202-204°C ;'H NMR 8H (d6-DMSO, 600 MHz): 2.17 (3H, d), 2.30 (3H, s), 2. 84 (3H, d), 3.0-3. 2 (6H, m), 3.60 (2H, m), 3.73 (3H, s), 4.01 (2H, s), 6.97 (1H, dd), 7.02 (1H, d), 7.09 (1H, s), 7.12 (2H, d), 7.20 (1H, t), 7.45 (2H, d), 7.49 (2H, d), 7.81 (2H, d), 7.85 (1H, s), 9.68 (1H, brs).

Table 1: X-Ray powder diffraction (XRPD) angles and d spacings for 7- [4- (3-Fluoro-4- methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3- benzazepinium p-toluenesulfonate Pos. [°2Th. J d-spacing [A] 3.5 25.5 9.6 9. 2 11.2 7.9 11.7 7.6 13.6 6.5 15.1 5.9 15.9 5.6 16.3 5.4 16.9 5.3 17.5 5.1 17.9 5.0 18.2 4.9 18.8 4.7 19.2 4.6 20.2 4. 4 20.4 4. 4 Pos. °2Th. d-s acin A 20.6 4.3 20.7 4.3 20.9 4.2 22.5 3.9 23.2 3.8 23.5 3. 8 24.1 3.7 24.4 3.6 26.3 3.4 27.3 3.3 27.6 3.2 28.0 3.2 30.8 2.9 31.5 2. 8 Data obtained for the tosylat is shown in Figures 1-3 and Table 1.

Example 4 7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1H-3-benzazepinium p-toluenesulfonate, monohydrate (E4)

Chlorotrimethylsilane (66 uL 0.52 mmol) was added to zinc granules (1.23 g, 18.75 mmol) in tetrahydrofuran (20.5 mL) and the suspension stirred for 30 minutes. 3-Fluoro-4-methyl- benzylbromide (1.52 g, 7.5 mmol) was added to the mixture over 15 minutes maintaining the temperature at 20-25°C and the reaction mixture stirred at ambient temperature for 90 minutes. Tetrakis (triphenylphosphine) palladium (0) (5.8 mg, 0.005 mmol) was added followed by a solution of 7- (4-Bromobenzenesulfonyl)-8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3- benzazepine (D4) (2.05 g, 5mmol) in tetrahydrofuran (20.5 mL) and the resulting mixture heated under reflux for 4 hours. The reaction was cooled to ambient temperature and 5% w/w aqueous sodium bicarbonate (20.5 mL) added. The resulting mixture was stirred for 15 minutes, filtered through celite and the phases of the filtrate separated. The organic phase was washed with 10% w/w aqueous sodium chloride (3 x 20.5 mL) and the resulting aqueous phases combined and extracted with ethyl acetate (20.5 mL). The two organic phases obtained were combined and treated with trithiocyanuric acid (4.43 mg, 0.025 mmol) for 1 hour at 18-25°C. The suspension was filtered through celite and the filtrate extracted with water (2 x 20.5 mL). The aqueous phases were combined and treated with p-toluenesulfonic acid monohydrate (952 mg, 5 mmol). The solution was concentrated under vacuum, the resulting slurry cooled to ambient temperature and stirred for 2 hours. The product was filtered, washed with water (10.25 mL) and dried under vacuum at 40°C to yield the title product (E4) as a white solid (2.04 g). Mp 198.5-200. 5°C ; MH+454 ; 1H NMR 8H (DMSO-d6) 2.18 (3H, s), 2.30 (3H, s), 2.84 (3H, s), 2.95-3. 65 (8H, br m), 3.73 (3H, s), 4.01 (2H, d), 6.96- 7.04 (2H, m), 7.11-7. 14 (3H, m), 7.18 (1H, t), 7.45-7. 50 (4H, m), 7.80-7. 85 (3H, m), 9.70 (1H, br s).

Table 2: XRPD angles and d spacings for 7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]- 8-methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepinium p-toluenesulfonate, monohydrate

Pos. [°2Th.] d-spacing [A] 3.3 27.1 9.4 9.3 10.4 8.5 11.7 7. 5 13.7 6.5 15.7 5.6 16.0 5.5 17.5 5.1 17.8 5.0 18.6 4.8 18.9 4.7 19.6 4.5 19.8 4.5 20.1 4.4 21.1 4. 2 21. 3 4. 2 Pos. [°2Th.] d-s acin A 22.0 4.0 22.4 4.0 23.5 3.8 23.7 3.7 25.1 3.5 25.2 3.5 27.1 3.3 28.3 3.2 28.4 3.1 29.4 3.0 29.7 3.0 31.5 2.8 31.6 2.8 33. 1 2. 7 Data obtained for the tosylat, monohydrate is shown in Figures 4-6 and Table 2.

X-Ray Powder Diffraction X-Ray Powder Diffraction (XRPD) analysis was performed on a Philips X'pert Pro powder diffractometer, using an X'Celerator detector. The acquisition conditions were; radiation: Cu K generator tension: 40 kV, generator current: 45mA, start angle : 2.0 °20, end angle : 40.0 °26, step size: 0.0167 °20, time per step: 31.75 seconds. The sample was prepared using silicon wafer technique.

Raman Spectroscopy Raman spectra were recorded in an NMR tube using a Nicolet 960 E. S. P. FT-Raman spectrometer, at 4 cm-1 resolution with excitation from a Nd: V04 laser (1064 nm) with a power output of 400mW. An absolute threshold of 0.5 and sensitivity of 65% were applied for the purpose of peak selection.

Differential Scanning Calorimetry (DSC) DSC thermograms were recorded using a Thermal Analysis DSC Q1000. The sample was heated at 10 °C min'in an open pan.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.